Vitamins are a diverse group of organic compounds, required in small amounts in the diet. They have distinct biochemical roles, often as coenzymes, and are either not synthesized or synthesized only in limited amounts by human cells. Vitamins are classified according to their solubility, either fat-soluble or water-soluble. The physiological processes dependent on vitamin-requiring reactions include many aspects of intermediary metabolism, vision, bone formation, and blood coagulation, and vitamin deficiencies are associated with a correspondingly diverse and severe group of diseases.
Water-soluble vitamins include ascorbate (vitamin C) and the members of the B group: thiamin (vitamin B1), riboflavin (B2), niacin (B3), pantothenate (B5), pyridoxine (B6), biotin (B7), folate (B9), and cobalamin (B12). Metabolic processes annotated here include the synthesis of thiamin pyrophosphate (TPP) from thiamin (B1), the synthesis of FMN and FAD from riboflavin (B2), the synthesis of nicotinic acid (niacin - B3) from tryptophan, the synthesis of Coenzyme A from pantothenate (B5), and features of the metabolism of folate (B9).
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Folates are essential cofactors that provide one-carbon moieties in various states of reduction for biosynthetic reactions. Processes annotated here include transport reactions by which folates are taken up by cells and moved intracellularly, folate conjugation with glutamate (required for folate retention within a cell), and some of the key reactions in the generation of reduced folates and one-carbon derivatives of folate.
Nicotinate (niacin) and nicotinamide are precursors of the coenzymes nicotinamide-adenine dinucleotide (NAD+) and nicotinamide-adenine dinucleotide phosphate (NADP+). When NAD+ and NADP+ are interchanged in a reaction with their reduced forms, NADH and NADPH respectively, they are important cofactors in several hundred redox reactions. Nicotinate is synthesized from 2-amino-3-carboxymuconate semialdehyde, an intermediate in the catabolism of the essential amino acid tryptophan (Magni et al. 2004).
A methyl group from 5-methyltetrahydrofolate is transferred to homocysteine (HCYS) via a meCbl intermediate, forming methionine (L-Met) (Leclerc et al. 1996).
The conjugation of cysteine (Cys) and 4'- phosphopantothenate (PPanK) to form 4-phosphopantothenoylcysteine (PPC) , coupled to the conversion of ATP to AMP and pyrophosphate, is catalyzed by cytosolic phosphopantothenate-cysteine ligase (PPCS aka Phosphopantothenoylcysteine synthase or PPC synthase). Mammalian PPCS prefers ATP to CTP, unlike the E. coli ortholog (Daughtery et al. 2002; Manoj et al. 2003).
The adenylyl transferase activity of bifunctional coenzyme A synthase (COASY) catalyzes the transfer of an adenylyl group from ATP to pantetheinephosphate (PPANT) to form dephospho-Coenzyme A (DP-CoA) (Daugherty et al. 2002). The enzyme is associated with the mitochondrial outer membrane (Zhyvoloup et al. 2003).
Cytosolic thiamin pyrophosphokinase (TPK1) catalyzes the reaction of thiamin (THMN) and ATP to form thiamin diphosphate (ThDP aka thiamin pyrophosphate) and ADP. ThDP is an active cofactor for transketolase, pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, enzymes involved in glycolysis and energy production. The gene encoding the human enzyme has been cloned and its protein product has been shown to have TPK1 activity (Nosaka et al. 2001; Zhao et al. 2001). Its homodomeric structure and association with Mg2+ are inferred from properties of the homologous yeast enzyme (Baker et al. 2001).
The kinase activity of CoA synthase (COASY) catalyzes the phosphorylation of dephospho-CoA to form Coenzyme A (CoA-SH). The enzyme is located in the mitochondrial outer membrane (Daugherty et al. 2002; Zhyvoloup et al. 2003).
The decarboxylation of phosphopantothenoylcysteine (PPC) to 4'-phosphopantetheine (PPANT) is carried out by phosphopantothenoylcysteine decarboxylase (PPCDC). PPCDC is cytosolic and exists as a homotrimer, binding one FMN cofactor per subunit. While a second isoform has been inferred from large-scale sequnceing studies, it lacks the protein's FMN-binding domain and would thus appear to be nonfunctional if it is expressed.
Pantothenate kinase 2 catalyzes the reaction of ATP and pantothenate to form ADP and phosphopantothenate. While pantothenate kinase 2 co-purifies with mitocondria, its precise location within the mitochondrion has not been established (Hortnagel et al. 2003; Johnson et al. 2004). Recent work by Leonardi et al. (2007) supports a model in which the enzyme is located in the intermembrane space, hence freely accessible to small molecules from the cytosol.Pantothenate is phosphorylated by pantothenate kinase (PANK). Deficiencies in PANK2 cause a progressive neurodegenerative disorder associated with iron accumulation in the brain, but the relationship between disease symptoms and pantothenate metabolism remains unclear (Zhou et al. 2001; Zhang et al. 2006).
FMN can be phosphorylated and adenylated to produce the second cofactor from riboflavin origins, flavin adenine dinucleotide (FAD). The enzyme responsible , FMN adenylyltransferase (FLAD1 aka FAD synthase), is cytosolic and transfers a phosphate and an adenyl group from ATP to form FAD.
Cytosolic, homodimeric tartrate-resistant acid phosphatase type 5 (TRAP) catalyzes the hydrolysis of flavin mononucleotide (FMN) to yield riboflavin (RIB) and orthophosphate.
Phosphatase action on flavin adenine dinucleotide (FAD) can reform flavin mononucleotide (FMN). The enzyme performing the reaction is nucleotide pyrophosphatase (ENPP1) and it exists as a homodimer on the plasma membrane.
Phosphorylation of riboflavin (RIB) results in the formation of the first cofactor, flavin mononucleotide (FMN). This reaction is catalyzed by riboflavin kinase (RFK), a cytosolic enzyme existing as a monomer. It utilizes either zinc or magnesium ions in the reaction.
Cytosolic omega class glutathione transferases (GSTO1 and GSTO2) catalyze the reaction of dehydroascorbate (DHvitC) and glutathione (GSH) to form ascorbate (VitC) and oxidized glutathione (GSSG). The GSTO enzymes occur as homodimers (Board et al. 2000), and while both have dehydroascorbate reductase activity in vitro, that of GSTO2 is much greater than that of GSTO1 (Schmuck et al. 2005). Polymorphisms affecting the activities of the two enzymes have been described (Whitbread et al. 2005).
The uptake of extracellular dehydroascorbate into the cytosol is mediated by GLUT1 and GLUT3 associated with the plasma membrane (Rumsey et al. 1997, 2000). This process may play a significant role in ascorbate utilization in the central nervous system (Agus et al. 1997). The process is efficiently competitively inhibited by glucose, leading to the suggestion that inhibited dehydroascorbate uptake may contribute to the pathology of diabetes (Liang et al. 2001; Rumsey et al. 2000).
Cytochrome b5 reductase (CYB5R3) catalyzes the reduction of cytosolic ferric CYB5A (CYB5A:ferriheme) to ferrous CYPB5A (CYB5A:heme), coupled to the conversion of NADH to NAD+ (Shirabe et al. 1995). CYB5R3 is associated with the outer mitochondrial membrane via a myristoyl group added post-translationally to glycine residue 2 of the protein (Borgese et al. 1993).
The reduction of cytosolic semidehydroascorbate (SDA) to ascorbate (vitC) is catalyzed by cytochrome B5 (CYB5A) associated with the mitochondrial outer membrane. In the course of the reaction, the heme iron of the cytochrome is oxidized (Linster & Van Schaftingen 2007, Shirabe et al. 1995).
The plasma membrane-associated transport proteins SVCT1 and SVCT2 are each capable of mediating the uptake of one molecule of ascorbate (VitC) and two sodium ions from the extracellular space to the cytosol (Daruwala et al. 1999; Rajan et al. 1999; Wang et al. 1999). In the body SVCT2 is expressed in most tissues, while SVCT1 is largely confined to epithelial cells (Liang et al. 2001). SVCT2 may mediate fetal uptake of ascorbate from the maternal circulation (Rajan et al. 1999). The transporters responsible for its uptake from the small intestine and for its release from enterocytes into the circulation have not been identified, although both SVCT1 and 2 are expressed in intestinal cells.
Cytosolic AASDHPPT (alpha-aminoadipic semialdehyde dehydrogenase-phosphopantetheinyl transferase) catalyzes the transfer of a phosphopantetheine moiety from coenzyme A to serine 2156 within the ACP domain of FAS (fatty acyl synthase). Only a single human enzyme with phosphopantetheinyl transferase activity has been identified, and its broad substrate specificity suggests that it may be responsible as well for the postranslational modification of enzymes of lysine catabolism (Joshi et al. 2003; Praphanphoj et al. 2001).
Cytosolic pantothenate kinases catalyze the reaction of ATP and pantothenate to form ADP and phosphopantothenate. This enzymatic activity has been demonstrated in crude cell extracts for two isoforms of mouse pantothenate kinase 1 (Rock et al. 2002) and for their human homologues (Ramaswamy and 2004). Two additional human genes, PANK3 and PANK4, encode closely related proteins but pantothenate kinase activity has not been demonstrated experimentally for them (Leonardi et al. 2005; Zhou et al. 2001).
The plasma membrane-associated transport protein SLC5A6 (SMVT) mediates the uptake of one molecule of pantothenate (PanK) and two sodium ions from the extracellular space to the cytosol. Limited Northern blotting studies suggest that SLC5A6 is widely expressed, and abundant in placenta and small intestine. SLC5A6 may thus play a central role in pantothenate uptake. SLC5A6 also mediates the uptake of biotin and lipoate (Prasad et al. 1999, Wang et al. 1999). PDZ domain-containing protein 11 (PDZD11 aka AIPP1) is a cytosolic protein with a single PDZ domain which can bind to the C-terminal class 1 PDZ binding motif of SLC5A6, resulting in a significant induction of vitamin uptake over that with SLC5A6 alone (Nabokina et al. 2011).
Graves disease carrier protein (SLC25A16), associated with the inner mitochondrial membrane, mediates the transport of cytosolic coenzyme A (CoA-SH) into the mitochondrial matrix. Evidence for this event is indirect. The protein has the sequence motifs expected for a transport protein, and yeast cells deficient in its homologue, Leu5p, fail to accumulate mitochondrial CoA-SH and can be rescued by expression of SLC25A16. At the same time, neither the yeast nor the human protein has been shown directly to function as a transporter (Prohl et al. 2001, Leonardi et al. 2007).
The plasma membrane-associated transport protein SLC5A6 (aka sodium-dependent multivitamin transporter, SMVT) mediates the uptake of one molecule of biotin (Btn) and two sodium ions from the extracellular space to the cytosol. Limited Northern blotting studies suggest that SLC5A6 is widely expressed and abundant in placenta, liver and small intestine. SLC5A6 may thus play a central role in Btn uptake from dietary sources. SLC5A6 also mediates the uptake of pantothenate and lipoate (Prasad et al. 1999, Wang et al. 1999, Balamurugan et al. 2003). PDZ domain-containing protein 11 (PDZD11 aka AIPP1) is a cytosolic protein with a single PDZ domain which can bind to the C-terminal class 1 PDZ binding motif of SLC5A6, resulting in a significant induction of vitamin uptake over that with SLC5A6 alone (Nabokina et al. 2011).
Two transport proteins, SLC19A2 (THTR1) and SLC19A3 (THTR2), associated with the plasma membrane, are each able to mediate the transport of extracellular thiamin into the cytosol. In the body, both transporters are widely distributed, and both are abundant in kidney and intestinal epithelia, consistent with their involvement in thiamin uptake under physiological conditions (Ashokkumar et al. 2006; Said et al. 2004; Subramanian et al. 2006 - J Biol Chem). The observation that mutations in SLC19A2 (THTR1) cause a progressive disorder that can be partially reversed by treatment with high doses of thiamin likewise suggests a role for this protein in thiamin uptake under normal conditions (Diaz et al. 1999; Fleming et al. 1999; Labay et al. 1999).
Two features of this transport process remain incompletely understood, however. First, mutations in SLC19A3 cause a progressive disorder that is responsive to biotin treatment (Zhou et al. 2005), although studies of cultured cells indicate that the protein has no affinity for biotin (Subramanian et al. 2006 - Am J Physiol). Also, studies to date provide little information about the mechanism by which thiamin, once taken up by epithelial cells in the intestine and kidney, is released from these cells into the blood.
Biotin (Btn) acts as a coenzyme to 4 carboxylases which exist in their inactive apo forms. These apo-carboxylases are biotinylated to their active halo forms by the activity of biotin-protein ligase (HCLS) (Ingaramo & Beckett 2012, Hiratsuka et al. 1998, Bailey et al. 2010). HCLS is localised to the cytosol and mitochondrion so can perform this activity in either of these locations. Defects in HLCS causes holocarboxylase synthetase deficiency (HLCS deficiency aka biotin-responsive multiple carboxylase deficiency; MIM:253270). HLCS deficiency is an autosomal recessive disorder whereby deficient HLCS activity results in reduced activity of multiple carboxylases. Symptoms include metabolic acidosis, organic aciduria, lethargy, hypotonia, convulsions and dermatitis (Suzuki et al. 2005). Propionyl-CoA carboxylase is most likely functional as a dodecamer, composed of six Btn-containing alpha subunits (PCCA) and six beta subunits (PCCB). The exact order in which this complex is constructed is unknown.
Biotin (Btn) acts as a coenzyme to 4 carboxylases which exist in their inactive apo forms. In the cytosol, these apo carboxylases are biotinylated to their active halo forms by the activity of biotin-protein ligase (HCLS) (Ingaramo & Beckett 2012, Hiratsuka et al. 1998, Bailey et al. 2010). HCLS is localised to the cytosol and mitochondrion so can perform this activity in either of these locations. Defects in HLCS causes holocarboxylase synthetase deficiency (HLCS deficiency aka biotin-responsive multiple carboxylase deficiency; MIM:253270). HLCS deficiency is an autosomal recessive disorder whereby deficient HLCS activity results in reduced activity of multiple carboxylases. Symptoms include metabolic acidosis, organic aciduria, lethargy, hypotonia, convulsions and dermatitis (Suzuki et al. 2005). Methylcrotonoyl-CoA carboxylase is most likely functional as a dodecamer, composed of 6 Btn-containing alpha subunits (MCCC1) and six beta subunits (MCCC2). The exact order in which this complex is constructed is unknown.
Biotin (Btn) acts as a coenzyme to 4 carboxylases which exist in their inactive apo forms. In the cytosol, these apo-carboxylases are biotinylated to their active halo forms by the activity of biotin-protein ligase (HCLS) (Ingaramo & Beckett 2012, Hiratsuka et al. 1998, Bailey et al. 2010). HCLS is localised to the cytosol and mitochondrion so can perform this activity in either of these locations. Defects in HLCS causes holocarboxylase synthetase deficiency (HLCS deficiency aka biotin-responsive multiple carboxylase deficiency; MIM:253270). HLCS deficiency is an autosomal recessive disorder whereby deficient HLCS activity results in reduced activity of multiple carboxylases. Symptoms include metabolic acidosis, organic aciduria, lethargy, hypotonia, convulsions and dermatitis (Suzuki et al. 2005). Pyruvate carboxylase (PC) is homotetrameric, binds 1 Mn2+ and 1 Btn per PC subunit (Xiang & Tong 2008). The exact order in which this complex is constructed is unknown.
Biotin (Btn) acts as a coenzyme for 5 carboxylases that exist in their inactive apo forms. In the cytosol and mitochondrion, these apo-carboxylases are biotinylated to their active holo forms by the activity of biotin protein ligase (HCLS) (Ingaramo & Beckett 2012, Bailey et al. 2010, Hiratsuka et al. 1998). Defects in HLCS causes holocarboxylase synthetase deficiency (HLCS deficiency aka early-onset multiple carboxylase deficiency; MIM:253270). HLCS deficiency is an autosomal recessive disorder whereby deficient HLCS activity results in reduced activity of all five carboxylases. Symptoms include metabolic acidosis, organic aciduria, lethargy, hypotonia, convulsions and dermatitis (Suzuki et al. 2005). The first committed step in the synthesis of fatty acids is performed by the biotin-dependent enzyme acetyl CoA carboxylase [EC 6.4.1.2]. Acetyl CoA carboxylases 1 and 2 (ACACA and ACACB) have one Btn moiety covalently attached to each subunit (Abu-Elheiga et al. 1995). Eukaryotic acetyl-CoA carboxylases are heterodimers that can form catalytically active extended oligomers (Weatherly et al. 2004). Unlike the other biotin-dependent carboxylases that reside inside the mitochondrion, ACACA and B are located in the cytosol (shown here) and outer mitochondrial membrane respectively (Abu-Elheiga et al. 2000).
Transcobalamin (TCN, TC) is a vitamin B12-binding protein secreted by endothelial cells into plasma that facilitates the endocytosis of cobalamin (Cbl, vitamin B12) into hepatocytes or cells requiring Cbl. Two TCN genes, TCN1 (aka haptocorrin) and TCN2, code for functional proteins (TCI and TCII respectively) that can bind Cbl (Johnston et al. 1989, Quadros et al. 1986, Wuerges et al. 2006). TCII can be bound to between 10-30% of the total circulating Cbl, the remaining Cbl bound to TCI and not available for uptake by cells outside of the liver. TCII transports Cbl used by tissues. The role of TCI carrying between 70-90% of the Cbl serum fraction is unknown. Free Cbl can be taken up by passive diffusion but only at concentrations that are never achieved in the body.
In the mucosal cells of the distal ileum, in preparation for internalisation, the gastric intrinsic factor:cobalamin (GIF:Cbl) complex interacts with cubilin (CUBN). CUBN is a cotransporter facilitating uptake of lipoproteins, vitamins and iron (Matthews et al. 2007). CUBN is in complex with protein amnionless (AMN), a necessary component which directs subcellular localization and endocytosis of GIF:Cbl (Fyfe et al. 2004, Anderson et al. 2010). Defects in CUBN and AMN both cause recessive hereditary megaloblastic anemia 1 (RH-MGA1 aka MGA1 Norwegian type or Imerslund-Grasbeck syndrome, I-GS; MIM:261100). The resultant malabsorption of Cbl (vitamin B12) leads to impaired B12-dependent folate metabolism and ultimately impaired thymine synthesis and DNA replication (Aminoff et al. 1999, Kristiansen et al. 2000, Tanner et al. 2003, Densupsoontorn et al. 2012).
Once the receptor complex (TCII:Cbl:CD320) is internalised by endocytosis, the receptor (CD320) dissociates to return to the plasma membrane (Youngdahl-Turner et al. 1979).
Transcobalamin II (TCII, the product of the gene TCN2) degradation is necessary for cobalamin (Cbl) to be released from the complex and made available for binding to Cbl-dependant apoenzymes (Youngdahl-Turner et al. 1979). The TCII:Cbl complex translocates to lysosomes for degradation.
Gastric parietal cells secrete gastric intrinsic factor (GIF) which binds tightly to free cobalamin (Cbl) released from transcobalamin (TCN1, haptocorrin) in the proximal intestine (Matthews et al. 2007). Cbl must bind to GIF to be absorbed from the small intestine.
The ubiquitously-expressed CD320 antigen (CD320 aka transcobalamin receptor, TCblR) internalises TCII:Cbl by endocytosis after binding to it (Quadros et al. 2009, Quadros et al. 2005). Defects in CD320 cause methylmalonic aciduria type TCblR (MMATC aka methylmalonic aciduria; MIM:613646) (Quadros et al. 2010). The first patient identified had only methylmalonic aciduria, subsequent patients had both this and homocystinuria. There is so far no confirmed clinical consequence of this disorder; patients have somewhat elevated MMA and homocysteine levels but no consistent additional findings.
The cubilin:protein amnionless (CUBN:AMN) complex mediates the internalisation and endocytosis of gastric internal factor:cobalamin (GIF:Cbl) into mucosal cells of the distal ileum (Fyfe et al. 2004).
The probable lysosomal cobalamin transporter (LMBD1) is the most likely candidate to transport cobalamin (Cbl) from inside the lysosome to the cytosol (Rutsch et al. 2009). From here, Cbl can either be used to synthesise the essential cofactors for methionine synthase in the cytosol or methylmalonyl-CoA mutase in the mitochondria or, it can transported out of the cell to tissues that require Cbl. Defects in LMBRD1 (the gene that produces LMBD1) cause methylmalonic aciduria and homocystinuria type cblF (MMAHCF; MIM:277380), characterised biochemically by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) (Rutsch et al. 2009, Gailus et al. 2010).
Once in the lysosome, transcobalamin 2:cobalamin (TCII:Cbl) is degraded to release Cbl (Youngdahl-Turner et al. 1979). Cbl is ready to be exported out of the lysosome to the cytosol by the probable lysosomal cobalamin transporter (LMBRD1) (Rutsch et al. 2009). Once in the cytosol, Cbl can be used in the synthesis of the essential cofactors methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) as described in the steps above.
Cytosolic acetyl-CoA carboxylases 1 and 2 (Btn-ACACA/B:2Mn2+) are degraded proteolytically to biocytin (BCTN aka biotinyl-lysine) or small biotinyl peptides (not shown here) by an unknown protease (Chandler & Ballard 1985, Hymes & Wolf 1996, Hymes & Wolf 1999).
The mitochondrial holocarboxylases (hCBXs) propionyl-CoA carboxylase, methylcrotonoyl-CoA carboxylase and pyruvate carboxylase are degraded proteolytically to biocytin (BCTN aka biotinyl-lysine) or small biotinyl peptides (not shown here) (Chandler & Ballard 1985, Hymes & Wolf 1996, Hymes & Wolf 1999).
Human biotinidase (BTD, EC 3.5.1.12) (Cole et al. 1994) catalyzes the hydrolysis of biocytin (BCTN, aka biotinyl-lysine), a product of biotin dependent carboxylase degradation, to biotin (Btn) and lysine. As a result, Btn is again available to be used in the biotinylation of apo-carboxylases in the mitochondrion. BTD is both secreted from various cells and localised in the mitochondria (Wolf & Jensen 2005). BTD deficiency, an autosomal recessive disorder, results in a secondary Btn deficiency that leads to juvenile onset multiple carboxylase deficiency (MIM:253260) (Wolf et al. 1983).
Methylmalonic aciduria and homocystinuria type C protein (MMACHC aka cblC protein) is suggested to be involved in the binding and intracellular transport of cobalamin (Cbl aka vitamin B12). MMACHC can catalyse the removal of the "R" group (formally called the upper axial ligand) from Cbl (eg dealkylation of AdoCbl and MeCbl or decyanation of CNCbl) which can result in the reduction of Cbl (+3 oxidation state) to cob(II)alamin (B12r, vitamin B12r +2 oxidation state) (Hannibal et al. 2009). Cob(II)alamin is escorted by MMACHC to its destination enzyme partners in the mitochondria and cytosol.
Defects in MMACHC cause methylmalonic aciduria and homocystinuria type cblC (MMAHCC; MIM:277400). MMAHCC is the most common disorder of Cbl metabolism and is characterised by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MetCbl). Affected individuals may have developmental, haematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings (Lerner-Ellis et al. 2006).
Multidrug resistance-associated protein 1 (ABCC1, MRP1) can specifically mediate the ATP-dependant export of free cobalamin (Cbl aka vitamin B12) from small intestine cells to the portal vein (Shah et al. 2011).
In the proximal intestine, pancreatic enzymes degrade transcobalamin 1 (TCN1) to release cobalamin (Cbl). The two major pancreatic proteases are trypsins (PRSSs) and chymotrypsins (CTRBs) (Srikumar & Premalatha 2003, Nielsen et al. 2012).
Transcobalamin 1 (TCN1 aka haptocorrin, HC, TCII) is a glycoprotein produced by salivary glands in response to food ingestion (Johnston et al. 1989). TCN1 binds strongly to cobalamin (Cbl aka vitamin B12) and its essential function is protection of the acid-sensitive Cbl while it moves through the stomach. Once food is in the stomach, pepsin and the acidic pH degrade food proteins. Cbl is in its +3 oxidation state in dietary sources.
Exact details are unclear but it is assumed once the binding proteins (MMADCHC and MMADHC) deliver cob(II)alamin (B12r) to its cytosolic destination, they dissociate from it (Mah et al. 2013, Plesa et al. 2011, Deme et al. 2012).
MMACHC:cob(II)alamin (B12r, vitamin B12r) binding to methylmalonic aciduria and homocystinuria type D protein (MMADHC) represents a branch point in the targeted delivery of cob(II)alamin to either cytosolic or mitochondrial enzymes requiring this cofactor (Mah et al. 2013, Plesa et al. 2011, Deme et al. 2012). Both MMACHC and MMADHC are implicated in the intracellular transport of cobalamins but exact details of the mechanisms involved remain unclear.
Defects in MMADHC cause methylmalonic aciduria and homocystinuria type cblD (MMAHCD; MIM:277410), a disorder of Cbl metabolism characterised by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) (Coelho et al. 2008).
Methionine synthase reductase (MTRR) is involved in reducing cob(II)alamin (B12r) to methylcobalamin (MeCbl), the cofactor form used by methionine synthase (MTR). Regeneration of functional MTR requires reductive methylation via a reaction catalysed by MTRR in which S-adenosylmethionine (AdoMet, SAM) is used as a methyl donor. MTRR requires 1 FMN and 1 FAD per subunit for activity (Wolthers et al. 2007). MTRR exists in a stable complex with MTR, bound through their FMN-binding and C-terminal activation domains respectively (Wolthers & Scrutton 2007, Wolthers & Scrutton 2009).
When methionine synthase (MTR) is functioning properly, cobalamin (Cbl) is continuously shuttled between two forms, cob(I)alamin and MeCbl. There are 2 half reactions: transfer of a methyl group from 5-methyltetrahydrofolate (MTHF) to enzyme-bound cob(I)alamin to form MeCbl; and transfer of the methyl group from MeCbl to homocysteine (HYCS) to form AdoMet, methionine and regenerate cob(I)alamin. From time to time (every few hundred cycles), the enzyme-bound cobalamin is spontaneously oxidized to form cob(II)alamin. When this happens, MTRR in conjunction with MTR catalyzes the reductive methylation of cob(II)alamin to form MeCbl. If MTRR is defective, cob(II)alamin accumulates and methionine synthase is inactivated.
Defects in MTRR cause methylcobalamin deficiency type E (cblE; MIM:236270) (Wilson et al. 1999). Patients with cblE exhibit megaloblastic anemia and hyperhomocysteinemia. AdoMet is used as a methyl donor in many biological reactions and its demethylation produces homocysteine. Remethylation is carried out by MTR in conjunction with MTRR but in cblE patients, MTR-bound cobalamin cannot be reduced by defective MTRR to form a functional enzyme thus homocysteine accumulates. Mutations in MTRR that cause cblE include Leu576del (Leclerc et al. 1998) and S454L (Zavadakova et al. 2005). In terms of frequency, the most common MTRR mutation is a c.903+469C>T mutation which creates a novel splice site deep in an intron and results in inclusion of a 140-bp insertion in MTRR mRNA (Homolova et al. 2010). Wilson et al. showed that a 66A G polymorphism, resulting in an Ile22Met (I22M) substitution, is associated with susceptibility to folate sensitive neural tube defects (FS NTD; MIM:601634) (Wilson et al. 1999b, Doolin et al. 2002). Serum deficiency of vitamin B12 increased the effect.
A semi-synthetic form of the vitamin, cyanocobalamin (CNCbl, where a cyanide group is in the upper axial position), is produced from bacterial hydroxocobalamin and used in many pharmaceuticals, supplements and as a food additive. It is presumed to take the same route after ingestion as other forms of cobalamin (Cbl) (Randaccio et al. 2010). At this point in the pathway, CNCbl is reductively decyanated by methylmalonic aciduria and homocystinuria type C protein (MMACHC) to produce cob(II)alamin (B12r, vitaman B12r) and hydrogen cyanide (HCN) (Kim et al. 2008). Decyanation of CNCbl is required for it to be made available for conversion to active cofactors. MMACHC can remove the methyl (Me) and adenosyl (Ado) groups from MeCbl and AdoCbl respectively (not shown in this reaction), as well as CN from CNCbl.
Methionine synthase (MTR) catalyses the transfer of a methyl group from 5-methyltetrahydrofolate (MTHF) to homocysteine (HCYS) to then form methionine (L-Met). In the first step, MTR mediates the transfer of a methyl group from 5-methyltetrahydrofolate (MTHF) to cob(I)alamin (B12s, bound to the enzyme MTR) to form the cofactor methylcobalamin (MeCbl), the form that activates MTR (Leclerc et al. 1996). Defects in MTR cause methylcobalamin deficiency type G (cblG, methionine synthase deficiency; MIM:250940), an autosomal recessive inherited disease that causes mental retardation, macrocytic anemia, and homocystinuria (Leclerc et al. 1996).
Mitochondrial cob(I)yrinic acid a,c-diamide adenosyltransferase (MMAB) is an enzyme involved in the adenosylation of cob(I)alamin. In the first step, an unidentified reducing system reduces cob(II)alamin (B12r) to cob(I)alamin (B12s) (Fan & Bobik 2008, Leal et al. 2003).
Methylmalonic aciduria and homocystinuria type D protein (MMADHC) has sequence homology with a bacterial ATP-binding cassette transporter and contains a putative cobalamin binding motif and a putative mitochondrial targeting sequence which is thought to target cob(II)alamin (B12r) to the mitochondria (Stucki et al. 2012, Coelho et al. 2008). The actual mechanism of transport into the mitochondrion is unknown.
Mitochondrial cob(I)yrinic acid a,c-diamide adenosyltransferase (MMAB) is an enzyme involved in the adenosylation of cobalamin. MMAB transfers an adenosyl group from ATP to cob(I)alamin (B12s) to form adenosylcabalamin (AdoCbl) (Fan & Bobik 2008, Leal et al. 2003). Defects in MMAB cause methylmalonic aciduria type cblB (MMAB aka methylmalonic aciduria type B or vitamin B12-responsive methylmalonicaciduria of cblB complementation type; MIM:251110). Affected individuals have methylmalonic aciduria and metabolic ketoacidosis, despite a functional methylmalonyl-CoA mutase. In severe cases, newborns become severely acidotic and may die if acidosis is not treated promptly (Dobson et al. 2002).
Methylmalonyl-CoA mutase (MUT aka MCM) (Jansen et al. 1989) utilises adenosylcobalamin (AdoCbl) as a cofactor and catalyses interchange of a carbonyl-CoA group and a hydrogen atom in conversion of methymalonyl-CoA to form succinyl-CoA, a precursor for the citric acid cycle. MUT has a homodimeric structure and is located in the mitochondrial matrix. Defects in MUT cause methylmalonic aciduria type mut (MMAM; MIM:251000), an often fatal disorder of organic acid metabolism (Worgan et al. 2006).
Methylmalonic aciduria type A protein (MMAA) (Dobson et al. 2002) is thought to act as a chaperone to MUT and is suggested to play a dual role with regards to MUT protection and reactivation.
Defects in MMAA cause methylmalonic aciduria type cblA (MMAA aka methylmalonic aciduria type A or vitamin B12-responsive methylmalonicaciduria of cblA complementation type; MIM:251100). Affected individuals accumulate methylmalonic acid in the blood and urine and are prone to potentially life threatening acidotic crises in infancy or early childhood (Dobson et al. 2002, Lerner-Ellis et al. 2004).
The water-soluble vitamin riboflavin (RIB, vitamin B2) is essential for normal cellular functions. Three human riboflavin transporters mediate the transport of RIB into cells and play an important role in RIB homeostasis. The transporters are assigned to a new sub-family of the SLC superfamily; SLC52A1, SLC52A2 and SLC52A3 (aka RFVT1, RFVT2 and RFVT3 respectively). Solute carrier family 52, riboflavin transporter, member 1 (SLC52A1, RFVT1) is widely expressed with highest expression in the testis, placenta and small intestine (Yonezawa et al. 2008). Solute carrier family 52, riboflavin transporter, member 2 (SLC52A2, RFVT2) is highly expressed in brain, foetal brain and salivary gland (Yao et al. 2010). Solute carrier family 52, riboflavin transporter, member 3 (SLC52A3, RFVT3) transports riboflavin (RIB) from the lumen into small intestine epithelial cells (Yoshimatsu et al. 2014). Activity is inhibited by riboflavin analogues such as flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) (Yao et al. 2010). Defects in SLC52A3 cause Brown-Vialetto-Van Laere syndrome type 1 (BVVLS1; MIM:211530). BVVLS1 is a rare autosomal recessive neurologic disorder characterised by sensorineural hearing loss and a variety of cranial nerve palsies (Green et al. 2010). Defects in SLC52A3 also cause Fazio-Londe disease (FALOND; MIM:211500), a rare neurological disease characterised by progressive weakness of the muscles innervated by cranial nerves located at the lower brain stem (Bosch et al. 2011).
Aldehyde oxidase (AOX1) is a complex molybdo-flavoprotein that belongs to the xanthine oxidase family. It is active as a homodimer, with each monomer binding two distinct [2Fe2S] clusters, FAD and the molybdenum cofactor. AOX1 plays an important role in the metabolism of drugs based on its broad substrate specificity oxidising aromatic aza-heterocycles and aldehydes (Hartmann et al. 2012).
Methionine synthase reductase (MTRR) is involved in reducing cob(II)alamin (B12r) to cob(I)alamin (B12s), the cofactor form used by methionine synthase (MTR). MTRR requires 1 FMN and 1 FAD per subunit for activity (Wolthers et al. 2007). MTRR exists a stable complex with MTR, bound through their FMN-binding and C-terminal activation domains respectively (Wolthers & Scrutton 2007, Wolthers & Scrutton 2009).
Transcobalamin 1 (TCN1 aka haptocorrin, HC, TCI) is a glycoprotein produced by many cells including gastric cells in response to go food intake (Johnston et al. 1989). It can also bind a large fraction of cobalamin (Cbl) in the general circulation. No functional significance for this general binding is presently known (Quadros 2010, Alpers & Russel-Jones 1999 (in Chemistry and Biochemistry of B12, Banerjee 1999)).
Once biotinylated, three halocarboxylases (hCBXs) are localised to the mitochondrial matrix. The mechanism of transfer is still unclear. Pyruvate carboxylase (PC) is required for gluconeogenesis, lipogenesis, neurotransmitter synthesis and insulin secretion; Methylcrotonyl-CoA carboxylase (MCC) is required for amino acid metabolism; propionyl-CoA carboxylase (PCC) is required for odd-chain fatty acid oxidation (Ingaramo & Beckett 2012, Hiratsuka et al. 1998, Bailey et al. 2010).
Cytosolic acetyl-CoA carboxylases 1 and 2 (Btn-ACACA/B:2Mn2+) are degraded proteolytically to biocytin (BCTN aka biotinyl-lysine) or small biotinyl peptides (not shown here) by an unknown protease (Chandler & Ballard 1985, Hymes & Wolf 1996, Hymes & Wolf 1999).
Human biotinidase (BTD, EC 3.5.1.12) (Cole et al. 1994) catalyzes the hydrolysis of biocytin (BCTN, aka biotinyl-lysine), a product of biotin dependent carboxylase degradation, to biotin (Btn) and lysine. As a result, Btn is again available to be used in the biotinylation of apo-carboxylases in the mitochondrion. BTD is both secreted from various cells and localised in the mitochondria (Wolf & Jensen 2005). BTD deficiency, an autosomal recessive disorder, results in a secondary Btn deficiency that leads to juvenile onset multiple carboxylase deficiency (MIM:253260) (Wolf et al. 1983).
Biotin (Btn) acts as a coenzyme for 5 carboxylases that exist in their inactive apo forms. In the cytosol and mitochondrion, these apo-carboxylases are biotinylated to their active holo forms by the activity of biotin protein ligase (HCLS) (Ingaramo & Beckett 2012, Bailey et al. 2010, Hiratsuka et al. 1998). Defects in HLCS causes holocarboxylase synthetase deficiency (HLCS deficiency aka early-onset multiple carboxylase deficiency; MIM:253270). HLCS deficiency is an autosomal recessive disorder whereby deficient HLCS activity results in reduced activity of all five carboxylases. Symptoms include metabolic acidosis, organic aciduria, lethargy, hypotonia, convulsions and dermatitis (Suzuki et al. 2005). The first committed step in the synthesis of fatty acids is performed by the biotin-dependent enzyme acetyl CoA carboxylase [EC 6.4.1.2]. Acetyl CoA carboxylases 1 and 2 (ACACA and ACACB) have one Btn moiety covalently attached to each subunit (Abu-Elheiga et al. 1995). Eukaryotic acetyl-CoA carboxylases are heterodimers that can form catalytically active extended oligomers (Weatherly et al. 2004). Unlike the other biotin-dependent carboxylases that reside inside the mitochondrion, ACACA and B are located in the cytosol and outer mitochondrial membrane (shown here) respectively (Abu-Elheiga et al. 2000).
ATP-binding cassette sub-family D member 4 (ABCD4), originally thought to be localised to the peroxisomal membrane, has since been demonstrated to colocalise with the lysosomal proteins LAMP1 and LMBD1. Mutations modifying the ATPase domain of ABCD4 can affect its function and suggests a role in the intracellular transport of cobalamin (Cbl, aka vitamin B12) (Coelho et al. 2012). Further evidence for this role comes from mutation studies in ABCD4 that can cause methylmalonic aciduria and homocystinuria type CblJ (MAHCJ; MIM:614857), a disorder of Cbl metabolism characterised by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). This disease mimics the cblF defect caused by LMBRD1 mutations (Coelho et al. 2012).
Digestive proteases are synthesised and secreted by the pancreas as inactive zymogens whose activation occur in the duodenum. Activation of trypsin (PRSS1) within the pancreas before secretion is thought to be a major initiating factor in chronic pancreatitis. Chymotrypsin-C (CTRC) is a pancreatic serine protease that regulates activation and degradation of trypsinogens and procarboxypeptidases by targeting specific cleavage sites within their zymogen precursors. CTRC regulates trypsinogen activation and stability by two opposing cleavage sites: it can cleave cationic trypsinogen either at Phe18-Asp19 in the activation peptide, leading to enhanced autoactivation or at Leu81-Glu82 within the Ca2+-binding loop, resulting in degradation (the latter not shown here) (Batra et al. 2013).
Methylmalonyl CoA mutase (MUT aka MCM) (Jansen et al. 1989) utilises adenosylcobalamin (AdoCbl) as a cofactor and catalyzes interchange of a carbonyl-CoA group and a hydrogen atom in conversion of methylmalonyl CoA to form succinyl CoA, a precursor for the citric acid cycle. MUT has a homodimeric structure and is located in the mitochondrial matrix. Defects in MUT cause methylmalonic aciduria, mut type (MMAM; MIM:251000), an often fatal disorder of organic acid metabolism (Worgan et al. 2006).
Methylmalonic aciduria type A protein (MMAA) is thought to act as a chaperone to MUT, the enzyme which utilises adenosylcobalamin (AdoCbl) as a cofactor. MMAA is suggested to play a dual role with regards to MUT protection and reactivation. Some AdoCbl-dependent enzymes undergo suicide inactivation after catalysis due to the oxidative inactivation of Cbl. MMAA is thought to play a protective role to prevent MUT being inactivated in this way. After the catalytic cycle when MUT is inactive, MMAA increases the enzymatic activity of MUT through exchange of the damaged cofactor. Whether this happens via GTP-mediated hydrolysis is unknown at present (Takahashi-Iniguez et al. 2011, Froese et al. 2010). Bacterial AdoCbl-containing enzymes possess reactivating factors which release the inactivated cofactor to allow the resulting apoenzyme to reconstitute into an active form. A bacterial orthologue of MMAA, MeaB, forms a stable complex with MUT and plays a role in its protection and reactivation (Padovani & Banerjee 2006).
Defects in MMAA cause methylmalonic aciduria type cblA (cblA aka methylmalonic aciduria type A or vitamin B12-responsive methylmalonicaciduria of cblA complementation type; MIM:251100). Affected individuals accumulate methylmalonic acid in the blood and urine and are prone to potentially life threatening acidotic crises in infancy or early childhood (Dobson et al. 2002, Lerner-Ellis et al. 2004).
Mitochondrial thiamine pyrophosphate carrier (SLC25A19, DNC, MUP1) was originally thought to be a deoxyribonucleotide (DNC) carrier but has since been identified from enzyme kinetics, gene knockout studies and clinical samples from Amish Microcephaly (MCPHA) patients, to be a transporter of thiamine pyrophosphate (ThDP) into mitochondria (Kang & Samuels 2008). ThDP is a cofactor for the mitochondrial enzymes pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched chain amino acid dehydrogenase. The biochemical phenotype of MCPHA may be attributable to decreased activity of these enzymes (Siu et al. 2010).
Vanin (VNN1) is a membrane pantetheine hydrolase or pantetheinase (EC 3.56.1.-) (Maras et al. 1999, Martin et al. 2001), part of a cluster of three human orthologous genes (VNN1, VNN2, VNN3) on Chr. 6q22-24 (Kaskow et al. 2012, Boersma et al. 2014). VNN3 is a pseudogene in humans. Vanins catalyse the hydrolysis of pantetheine to pantothenic acid (PanK, vitamin B5) and cysteamine (2AET), a powerful anti-oxidant. PanK is the initial substrate for the synthesis of Coenzyme A (CoA-SH).
Coenzyme A (CoA-SH) in serum can be hydrolysed by ectonucleotide pyrophosphatases (ENPPs) (Goding et al. 2003), which have pantothenate kinase activity. The products of this are adenosine 3',5'-bismonophosphate (PAP) and 4′-phosphopantetheine (PPANT), which is able to translocate into cells providing an alternative source for intracellular coenzyme A biosynthesis (Srinivasan et al. 2015).
While the biosynthesis of the molybdenum cofactor for sulfite oxidase is finished after molybdenum ion insertion, human xanthine oxidase and aldehyde oxidase will only show activity with this cofactor when one of the oxygens bound to molybdenum is replaced with sulfur. The exchange is catalyzed by the MOCOS cysteine desulfurase (Ichida et al, 2001).
In order to get a sulfur atom for subsequent sulfuration reactions, cysteine is first desulfurated by NFS1 which transfers it onto a cysteine of MOCS3, yielding a protein persulfide (Marelja et al, 2008).
Gephyrin, which stabilizes receptors on neuronal membranes, also catalyzes the transfer of a molybdenum ion onto the cofactor. The mechanism was elucidated in plants but, as the pathway is highly conserved, human gephyrin can complement missing plant proteins. Doubts remain about the actual molybdenum donor, probably molybdate, and whether a copper ion is possibly bound and removed (Stallmeyer et al, 1999).
GTP cyclizes in a reaction involving radicals of S-adenosylmethionine, catalyzed by the iron-sulfur cluster dimeric MOCS1. The intermediate result is called precursor Z (Hanzelmann et al, 2002; Hanzelmann et al, 2004).
Sulfur transfer onto MOCS2A is closely preceded by its adenylylation and deadenylylation. After release of MOCS2A-CO-S(1-), two cysteines on MOCS3 form a disulfide bridge. This means that MOCS3 has to be reduced to be able to participate in the next round. The reducing agent is not known (Marelja et al, 2008).
After the MOCS2A dimer is loaded with two sulfur atoms, their sequential deposition on the precursor Z molecule, with ring cleavage, is catalyzed by the MOCS2B half of the MOCS2 tetramer (Leimkuhler et al, 2003; Wuebbens & Rajagopalan, 2002).
Pyridoxal kinase (PDXK) catalyzes the ATP-dependent phosphorylation of pyridoxamine (PXA) to form pyridoxamine phosphate (PXAP) (Lee et al. 2000, di Salvo et al. 2004).
Pyridoxal kinase (PDXK) catalyzes the ATP-dependent phosphorylation of pyridoxine (PDX) to form pyridoxine phosphate (PDXP) (Lee et al. 2000, di Salvo et al. 2004).
Pyridoxal kinase (PDXK) catalyzes the ATP-dependent phosphorylation of pyridoxal (PXL) to form pyridoxal 5'-phosphate (PXLP) (Lee et al. 2000, di Salvo et al. 2004).
Thiamin triphosphate (ThTP) can transfer phosphate to a few proteins. Animal tissues contain a membrane-associated as well as a soluble thiamine triphosphatase that can dephosphorylate ThTP. Only the soluble enzyme was characterized in calf (Lakaye et al, 2002).
Thiamin triphosphate (ThTP) is believed to be synthesized from thiamin diphosphate (ThDP), catalyzed by ThDP kinase (TDPK), an enzyme that remains poorly characterized (Nishino et al, 1983).
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cob(II)alamin
reductaseAnnotated Interactions
Two features of this transport process remain incompletely understood, however. First, mutations in SLC19A3 cause a progressive disorder that is responsive to biotin treatment (Zhou et al. 2005), although studies of cultured cells indicate that the protein has no affinity for biotin (Subramanian et al. 2006 - Am J Physiol). Also, studies to date provide little information about the mechanism by which thiamin, once taken up by epithelial cells in the intestine and kidney, is released from these cells into the blood.
Defects in MMACHC cause methylmalonic aciduria and homocystinuria type cblC (MMAHCC; MIM:277400). MMAHCC is the most common disorder of Cbl metabolism and is characterised by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MetCbl). Affected individuals may have developmental, haematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings (Lerner-Ellis et al. 2006).
Defects in MMADHC cause methylmalonic aciduria and homocystinuria type cblD (MMAHCD; MIM:277410), a disorder of Cbl metabolism characterised by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) (Coelho et al. 2008).
When methionine synthase (MTR) is functioning properly, cobalamin (Cbl) is continuously shuttled between two forms, cob(I)alamin and MeCbl. There are 2 half reactions: transfer of a methyl group from 5-methyltetrahydrofolate (MTHF) to enzyme-bound cob(I)alamin to form MeCbl; and transfer of the methyl group from MeCbl to homocysteine (HYCS) to form AdoMet, methionine and regenerate cob(I)alamin. From time to time (every few hundred cycles), the enzyme-bound cobalamin is spontaneously oxidized to form cob(II)alamin. When this happens, MTRR in conjunction with MTR catalyzes the reductive methylation of cob(II)alamin to form MeCbl. If MTRR is defective, cob(II)alamin accumulates and methionine synthase is inactivated.
Defects in MTRR cause methylcobalamin deficiency type E (cblE; MIM:236270) (Wilson et al. 1999). Patients with cblE exhibit megaloblastic anemia and hyperhomocysteinemia. AdoMet is used as a methyl donor in many biological reactions and its demethylation produces homocysteine. Remethylation is carried out by MTR in conjunction with MTRR but in cblE patients, MTR-bound cobalamin cannot be reduced by defective MTRR to form a functional enzyme thus homocysteine accumulates. Mutations in MTRR that cause cblE include Leu576del (Leclerc et al. 1998) and S454L (Zavadakova et al. 2005). In terms of frequency, the most common MTRR mutation is a c.903+469C>T mutation which creates a novel splice site deep in an intron and results in inclusion of a 140-bp insertion in MTRR mRNA (Homolova et al. 2010). Wilson et al. showed that a 66A G polymorphism, resulting in an Ile22Met (I22M) substitution, is associated with susceptibility to folate sensitive neural tube defects (FS NTD; MIM:601634) (Wilson et al. 1999b, Doolin et al. 2002). Serum deficiency of vitamin B12 increased the effect.
Methylmalonic aciduria type A protein (MMAA) (Dobson et al. 2002) is thought to act as a chaperone to MUT and is suggested to play a dual role with regards to MUT protection and reactivation.
Defects in MMAA cause methylmalonic aciduria type cblA (MMAA aka methylmalonic aciduria type A or vitamin B12-responsive methylmalonicaciduria of cblA complementation type; MIM:251100). Affected individuals accumulate methylmalonic acid in the blood and urine and are prone to potentially life threatening acidotic crises in infancy or early childhood (Dobson et al. 2002, Lerner-Ellis et al. 2004).
Methylmalonic aciduria type A protein (MMAA) is thought to act as a chaperone to MUT, the enzyme which utilises adenosylcobalamin (AdoCbl) as a cofactor. MMAA is suggested to play a dual role with regards to MUT protection and reactivation. Some AdoCbl-dependent enzymes undergo suicide inactivation after catalysis due to the oxidative inactivation of Cbl. MMAA is thought to play a protective role to prevent MUT being inactivated in this way. After the catalytic cycle when MUT is inactive, MMAA increases the enzymatic activity of MUT through exchange of the damaged cofactor. Whether this happens via GTP-mediated hydrolysis is unknown at present (Takahashi-Iniguez et al. 2011, Froese et al. 2010). Bacterial AdoCbl-containing enzymes possess reactivating factors which release the inactivated cofactor to allow the resulting apoenzyme to reconstitute into an active form. A bacterial orthologue of MMAA, MeaB, forms a stable complex with MUT and plays a role in its protection and reactivation (Padovani & Banerjee 2006).
Defects in MMAA cause methylmalonic aciduria type cblA (cblA aka methylmalonic aciduria type A or vitamin B12-responsive methylmalonicaciduria of cblA complementation type; MIM:251100). Affected individuals accumulate methylmalonic acid in the blood and urine and are prone to potentially life threatening acidotic crises in infancy or early childhood (Dobson et al. 2002, Lerner-Ellis et al. 2004).
cob(II)alamin
reductase